Fri Dec 02 2022

76 articles - From Friday Nov 25 2022 to Friday Dec 02 2022

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Guidelines

Guidelines and related publications, position statements, white papers, technical reviews, consensus statements, etc…

Blood Adv

Comparison and validation of the 2022 European LeukemiaNet guidelines in acute myeloid leukemia.

The updated ELN 2022 guidelines better stratify survival, namely between patients with intermediate or adverse-risk AML treated with IC. The increased complexity of risk stratification with inclusion of additional cytogenetic and molecular aberrations necessitates clinical workflows simplifying risk stratification.

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Leukemia

Diagnostics in Waldenström's macroglobulinemia: a consensus statement of the European Consortium for Waldenström's Macroglobulinemia.

In this paper, we present the consensus recommendations and laboratory requirements for the diagnosis of WM developed by the European Consortium of Waldenström's Macroglobulinemia (ECWM), for both clinical practice as well as the research/academical setting. We provide the procedures for multiparametric flow cytometry, fluorescence in situ hybridization and molecular tests, and with this offer guidance for a standardized diagnostic work-up and methodological workflow of patients with IgM monoclonal gammopathy of uncertain significance, asymptomatic and symptomatic WM.

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Meta-analysis

meta-analyses and systematic reviews

Haematologica

Investigational venetoclax combination therapy in acute myeloid leukemia - a systematic review and meta-analysis.

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Leukemia

Retraction Note: Prognostic models for chronic lymphocytic leukemia (CLL): a systematic review and meta-analysis.

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Thromb Haemost

Diagnostic accuracy of V/Q and Q SPECT/CT in patients with suspected pulmonary embolism: a systematic review and meta-analysis.

V/Q SPECT/CT has high sensitivity and specificity for the diagnosis of acute PE, meanwhile Q SPECT/CT has high sensitivity but limited specificity for the diagnosis of PE. Management studies will conclusively ascertain the actual role of SPECT/CT in the diagnostic workup of patients with suspected acute PE.

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Original articles

RCT, clinical trials, retrospective studies, etc…

Ann Oncol

Results of the c-TRAK TN trial: a clinical trial utilising ctDNA mutation tracking to detect molecular residual disease and trigger intervention in patients with moderate and high-risk early stage triple negative breast cancer.

c-TRAK-TN is the first prospective study to assess whether ctDNA assays have clinical utility in guiding therapy in TNBC. Patients had a high rate of metastatic disease on ctDNA detection. Findings have implications for future trial design, emphasising the importance of commencing ctDNA testing early, with more sensitive and/or frequent ctDNA testing regimes.

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Blood

Activation of the PP2A-B56a heterocomplex synergizes with venetoclax therapies in AML through BCL2 and MCL1 modulation.

Finally, PP2A targeting increases the efficacy of the clinically approved venetoclax and azacitidine combination in vitro, in primary cells, and in an AML patient-derived xenograft model. These preclinical results provide a scientific rationale for testing PP2A-activating drugs with venetoclax combinations in AML.

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Associations of clonal haematopoiesis with recurrent vascular events and death in patients with incident ischemic stroke.

D358A). The CH mutation profile is accompanied by a pro-inflammatory profile opening new avenues for preventive precision medicine approaches to resolve the self-perpetuating cycle of inflammation and clonal expansion.

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DDX41-associated susceptibility to myeloid neoplasms.

Several aspects of deleterious germline DDX41 alleles are noteworthy: (i) Certain variants are common in particular populations; (ii) MNs develop at older ages typical of de novo disease, challenging the paradigm that inherited cancer risk always causes disease in young people; (iii) Despite equal frequencies of these variants in men and women, men progress to MNs more frequently, suggesting a gender-specific effect on myeloid leukemogenesis; and (iv) Individuals with deleterious germline DDX41 variants develop acute severe graft versus host disease after allogeneic hematopoietic cell transplantation with wild-type donors more than others unless they receive post-transplant cyclophosphamide, suggesting a pro-inflammatory milieu that stimulates donor-derived T-cells. Biochemical studies and animal models have identified DDX41's ability to interact with double stranded DNA and RNA:DNA hybrids with roles in mRNA splicing, rRNAs/snoRNAs processing, and modulation of innate immunity, disruption of which could promote inflammation and drive tumorigenesis.

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The Spectrum of GATA2 Deficiency Syndrome.

Allogeneic hematopoietic stem cell transplantation (HSCT) results in reversal of the phenotype. There remain important unanswered questions in GATA2 deficiency including: 1) why do some family members remain asymptomatic despite harboring deleterious mutations in GATA2, 2) what are the genetic changes that lead to myeloid progression, 3) what causes the apparent genetic anticipation, and 4) what is the role of preemptive HSCT.

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Blood Adv

Activation priming and cytokine polyfunctionality modulate the enhanced functionality of low-affinity CD19 CAR T cells.

Our results show that CAT CAR T-cells exhibit enhanced activation to CD19 stimulation and a distinct transcriptomic and protein profile, with increased activation and cytokine polyfunctionality compared to FMC63 CAR T-cells. We demonstrate that the enhanced functionality of low-affinity CAT CAR T-cells is a consequence of an antigen-dependent priming induced by residual CD19-expressing B-cells present in the manufacture.

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Cord blood transplantation for nonmalignant disorders: early functional immunity and high survival.

We conclude that in the absence of a MRD, UCBT following myeloablative conditioning without serotherapy is an excellent curative option in young children with non-malignant disorders. This trial is registered at as NCT00950846.

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Incidence, Risk Factors, and Impact of Early Cardiac Toxicity after Allogeneic Hematopoietic Cell Transplantation.

ECE was associated with higher NRM (HR 4.68, P<0.001) and lower OS (HR 3.03, P<0.001). Considering that PTCY and TBI were predictors for ECE, and the impact of this complication on transplant mortality, the implementation of cardiac monitoring plans could be appropriate in patients receiving these medications.

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Paired bone marrow and peripheral blood samples demonstrate lack of widespread dissemination of some CH clones.

Importantly, we illustrate that CH, including clones with variant allele frequencies >10%, can be confined to specific bone marrow spaces and may be eliminated through surgical excision. Future work will define whether clones with somatic mutations in particular genes or clonal fractions of certain sizes are more likely to be localized or are slower to disseminate into the peripheral blood and other bony sites.

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Retained functional normal and preleukemic HSCs at diagnosis are associated to good prognosis in DNMT3Amut NPM1mut AMLs.

Furthermore, we show that while CD34+ subpopulations can contain next to LSCs also normal and/or pre-leukemic Hematopoietic Stem Cells (HSCs), this is not the case in CD34-GPR56+NKG2DL- enriched LSCs which thus can be isolated with high purity. Finally, we show that AML patients, who retain at time of diagnosis a reserve of normal and/or preleukemic HSCs in their bone marrow able to reconstitute immunocompromised mice, have significant longer relapse-free and overall survival compared to AML patients in whom functional HSCs are no longer detectable.

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Haematologica

DUSP22 rearranged ALK-negative ALCL is a pathogenetically distinct disease but can have variable clinical outcome.

Not available.

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DUSP22 rearrangement is associated with distinctive immunophenotype but not outcome in patients with systemic ALK-negative anaplastic large cell lymphoma.

However, in this cohort DUSP22-R was not associated with a better clinical outcome. Therefore, we suggest that current treatment guidelines for this subset of ALK-negative ALCL patients should not be modified at this time.

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IDH mutations are enriched in myelodysplastic syndrome patients with severe neutropenia and can be a potential for targeted therapy.

Not available.

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ALK-negative anaplastic large cell lymphoma with DUSP22 rearrangement has distinctive disease characteristics with better progression-free survival: a LYSA study.

There were 47/104 (45%) DUSP22-R and 2/93 (2%) TP63-R cases, including one DUSP22-R/TP63-R. DUSP22-R tumors showed more frequent CD3 expression (62% versus 35%, P=0.01), and less commonly a cytotoxic phenotype (27% versus 82%; P.

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CMV-specific T-cells following haploidentical transplants: reshaping a repertoire by half.

Not available.

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COVID-19 pandemic affects the ability of negative D-dimer to identify venous thromboembolism patients at low risk of recurrence: insights from Apidulcis study.

Not available.

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Hyperactive CREB subpopulations increase during therapy in paediatric B lineage acute lymphoblastic leukaemia.

The small molecule CREB inhibitor, 666-15, was shown to reduce CREB transcriptional activity and induce apoptosis in ALL PDX cells of varying cytogenetic subtypes in vitro, both in the presence and absence of stromal support. Together, these data suggest that the cAMP signalling pathway may provide an opportunity for MRD-directed therapy for many patients at high risk of relapse.

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Immune thrombotic thrombocytopenic purpura plasmas induce calcium- and IgG-dependent endothelial activation: correlations with disease severity.

Furthermore, two anti-ADAMTS13 monoclonal antibodies purified from iTTP patient B cells, but not serum from hereditary TTP, induced endothelial Ca2+ flux associated with Weibel-Palade bodies exocytosis in vitro, whereas inhibition of endothelial ADAMTS13 expression using small interference RNA, significantly decreased the stimulating effects of iTTP IgG. In conclusion, Ca2+-mediated endothelial cell activation constitutes a second "hit" of iTTP, is correlated with the severity of the disease and may constitute a possible therapeutic target.

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Landscape of immunoglobulin heavy chain gamma gene class switch recombination in patients with adult T-cell leukemia-lymphoma.

Not available.

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Measurable residual disease in acute lymphoblastic leukemia: methods and clinical context in adult patients.

However, new approaches to target MRD in patients with T-ALL remain an unmet need. As our MRD detection assays become more sensitive and expanding novel therapeutics enter clinical development, the future of ALL therapy will increasingly utilize MRD as a criterion to either intensify or modify therapy to prevent relapse or de-escalate therapy to reduce treatment-related morbidity and mortality.

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Measurable residual disease in chronic myeloid leukemia.

In this review we track this development including the international collaboration to standardize results, discuss the integration of molecular monitoring with other factors that affect patients' management, and describe emerging technology. Four case histories describe varying scenarios in which the accurate measurement of residual disease identified patients at risk of disease progression and allowed appropriate investigations and timely clinical intervention.

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Methotrexate cytarabine thiotepa rituximab (MATRix) chemoimmunotherapy for primary central nervous system lymphoma: a Toronto experience.

Not available.

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Targeting cytokine-induced leukemic stem cell persistence in chronic myeloid leukemia by IKK2-inhibition.

Not available.

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Targeting glutaminase is therapeutically effective in ibrutinib-resistant mantle cell lymphoma.

Moreover, telaglenastat showed anti-MCL synergy when combined with ibrutinib or venetoclax in vitro, which was confirmed using an MCL patient-derived xenograft model. Our study provides the first evidence that targeting GLS with telaglenastat, alone or in combination with ibrutinib or venetoclax, is a promising strategy to overcome ibrutinib resistance in MCL.

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Targetting glutaminase to starve lymphoma cells.

Not available.

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The present and future of measurable residual disease testing in acute myeloid leukemia.

The principles and practices surrounding MRD remain incompletely determined however and the genetic and immunophenotypic heterogeneity of AML may prevent a one-sizefits- al approach. Here, we review the current approaches to MRD testing in AML, discuss strengths and limitations, highlight recent technological advances that may improve such testing, and summarize ongoing initiatives to generate the clinical evidence needed to advance the use of MRD testing in patients with AML.

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What about (MG)US? Towards tailored testing in monoclonal gammopathies.

Not available.

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J Hematol Oncol

Proteogenomic insights into the biology and treatment of pancreatic ductal adenocarcinoma.

This proteogenomic dataset provided a valuable resource for researchers and clinicians seeking for better understanding and treatment of PDAC.

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Lancet Haematol

A sex-informed approach to improve the personalised decision making process in myelodysplastic syndromes: a multicentre, observational cohort study.

Interpretation Our results suggest that a sex-informed approach can improve the personalised decision making process in patients with myelodysplastic syndromes and should be considered in the design of clinical trials including low-risk patients. Funding European Union (Horizon 2020 and Transcan programs), Italian Association for Cancer Research, Italian Ministry of Health, and Italian Ministry of University and Research.

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Leukemia

Sustained activation of non-canonical NF-B signalling drives glycolytic reprogramming in doxorubicin-resistant DLBCL.

Collectively, our study uncovered novel molecular drivers of doxorubicin-induced resistance that are regulated by non-canonical NF-B pathway. We reveal new avenues of therapeutic targeting for R-CHOP-treated refractory/relapsed DLBCL patients.

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The ENL YEATS epigenetic reader domain critically links MLL-ENL to leukemic stem cell frequency in t(11;19) Leukemia.

Therapeutically, YEATS containing MLL-ENL leukemic cells display increased sensitivity to the YEATS inhibitor SGC-iMLLT compared to control AML cells. Our results demonstrate that the YEATS domain is important for MLL-ENL fusion protein-mediated leukemogenesis and exposes an "Achilles heel" that may be therapeutically targeted for treating t(11; 19) patients.

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Thromb Haemost

Association between Platelet Count and Treatment Effect of Ticagrelor or Prasugrel in Patients with Acute Coronary Syndromes.

In this analysis, incidence of ischemic and bleeding events at 12 months are comparable across quartiles of platelet count.

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Characterization of shear stress-mediated platelet dysfunction: An ex vivo model for extracorporeal circulation and a prospective clinical study.

However, no correlation between platelet degranulation and the occurrence of bleeding or thromboembolic events was observed. The used whole Blood flow cytometry with immediately fixation after drawing introduces a sensitive and easy-to-use method to determine platelet activation status and our data confirm that increased shear stress conditions under ECC can cause impaired degranulation of platelet.

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Reviews&Editorials

Plenty of the editorials are available as full text through the publisher website using the provided link

Ann Oncol

Moving towards individualized target-based therapies in acute myeloid leukemia.

We then propose approaches to optimize AML therapy in patients without directly actionable mutations. We conclude with a discussion on the emerging role of using measurable residual disease (MRD) to modify therapy based on the quality of response.

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Blood

A-two to the rescue.

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A balancing act between toxicity and deep response.

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APL: Nemo finds its sea anemone.

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Axi-cel in LBCL: fulfill two needs with one deed.

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Bumping CAR T cells up a Notch.

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Donor NK cells facilitate thymopoiesis in allo-BMT.

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Engineered platelets for clinical application: a step closer.

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GVHD prediction based on the microbiome.

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GVHD prevention by personalized nutrition.

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Platelets: out of shape and misbehaving.

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Blood Cancer J

Chronic lymphocytic leukemia treatment algorithm 2022.

The CLL-International Prognostic Index (CLL-IPI) remains the best-validated tool in predicting the time to first therapy among previously untreated patients, which guides selection for early intervention efforts. This review summarizes our current approach to the management of CLL, right from the time of diagnosis through relapsed disease.

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Haematologica

Introduction to the Series on Measurable Residual Disease.

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Leukemia

Biological drivers of clinical phenotype in myelofibrosis.

Recent data indicate that an innate immune deregulated state that hinges on the myddosome-IRAK-NFB axis favors the cytopenic myelofibrosis phenotype and offers opportunity for novel treatment approaches. We will review the biological and clinical features of the MF disease spectrum and associated treatment considerations.

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Miscellaneous

misc publications eg case reports, tools of the trade, images of the month, etc…

Am J Hematol

Allogeneic transplantation for chronic myeloid leukemia: I'm not dead yet!

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Hemophagocytic lymphohistiocytosis and hemozoin deposition in bone marrow macrophages in falciparum malaria.

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Pearson syndrome.

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Blood

Collins PJ, Fox CP, George L, et al. Characterizing EBV-associated lymphoproliferative diseases and the role of myeloid-derived suppressor cells. Blood. 2021;137(2):203-215.

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Diffuse Myocardial Fibrosis Occurs in Young Patients with Sickle Cell Anemia Despite Early Disease Modifying Therapy.

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Metastatic carcinoma mimicking hemophagocytic lymphohistiocytosis.

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Peripheral agglutination and hemolytic anemia following minor ABO-mismatch hematopoietic progenitor cell transplantation.

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Somatic TP53 mutations are pre-leukemic events in acute lymphoblastic leukemia.

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Blood Adv

DOACs in patients with brain cancers, promising but still a long way to go.

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Elevated RIPK3 correlates with disease burden in myelofibrosis.

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Narkhede M, Goyal G, Shea L, et al. Evaluating real-world treatment patterns and outcomes of mantle cell lymphoma. Blood Adv. 2022; 6(14):4122-4131.

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Haematologica

Generation of the first monoclonal antibody using mouse hybridomas.

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Images from the Haematologica Atlas of Hematologic Cytology: anaplastic large cell lymphoma, ALK-negative.

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Interleukin-1 receptor associated kinase 1/4 and bromodomain and extra-terminal inhibitions converge on NF-B blockade and display synergistic antitumoral activity in activated B-cell subset of diffuse large B-cell lymphoma with MYD88 L265P mutation.

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Modern real-world patterns of care and clinical outcomes among patients with newly diagnosed diffuse large-B cell lymphoma with or without double/triple-hit status in the United States.

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Structure-function analysis of the role of megakaryoblastic leukemia 1 in megakaryocyte polyploidization.

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Lancet Haematol

On the basis of sex: outcomes in myelodysplastic syndromes.

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Leukemia

Effect of ECOG performance status on outcomes in patients with acute myeloid leukemia and other high-grade myeloid neoplasms.

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Prognostic implications of mono-hit and multi-hit TP53 alterations in patients with acute myeloid leukemia and higher risk myelodysplastic syndromes treated with azacitidine-based therapy.

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Letters&Replies

Letters to the editors and authors’ replies

Am J Hematol

Fetal hemoglobin per erythrocyte (HbF/F-cell) after gene therapy for sickle cell anemia.

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Blood Cancer J

Bortezomib, Bendamustine and Dexamethasone vs Thalidomide, Bendamustine and Dexamethasone in Myeloma patients presenting with renal failure (OPTIMAL): a randomised, multi-centre phase II trial.

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Second symptomatic COVID-19 infections in patients with an underlying monoclonal gammopathy.

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J Hematol Oncol

Pre-exposure prophylaxis with tixagevimab/cilgavimab (AZD7442) prevents severe SARS-CoV-2 infection in recipients of allogeneic hematopoietic stem cell transplantation during the Omicron wave: a multicentric retrospective study of SFGM-TC.

Only one major adverse event was reported: an acute coronary syndrome, resolved without sequelae. Pending randomized controlled trial results, our data support the use of AZD7442 as pre-exposure prophylaxis for COVID-19 during Omicron wave in allo-HSCT patients who failed to develop humoral immunity to vaccination, to prevent severe and potentially lethal forms of SARS-CoV-2 infection.

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Leukemia

Optical Genome Mapping in MDS and AML as tool for structural variant profiling-comment and data update on Yang et al.: "High-resolution structural variant profiling of myelodysplastic syndromes by optical genome mapping uncovers cryptic aberrations of prognostic and therapeutic significance".

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